Antineoplastic chemotherapy currently encompasses several groups of drugs including alkylating agents, purine antagonists and antitumor antibiotics. Alkylating agents alkylate cell proteins and nucleic acids preventing cell replication, disrupting cellular metabolism and eventually leading to cell death. Typical alkylating agents are nitrogen mustard, cyclophosphamide and chlorambucil. Toxicities associated with alkylating agents treatment include nausea, vomiting, alopecia, hermorrhagic cystitis, pulmonary fibrosis and an increased risk of developing acute leukemia.
Purine, pyrimidine and folate antagonists are cell cycle and phase specific and, in order to promote an anti-tumor effect, they require cells to be in the cell replication cycle and in the DNA synthesis phase of replication. The purine antagonists such as 6-mercaptorpurine or 6-thioguanidine inhibit de novo purine synthesis and interconversion of purines. The pyrimidine antagonists, such as cytarabine, -fluorouracil or floxuridine inhibit DNA synthesis by inhibiting deoxycytidylate kinase and DNA polymerase.
Folate antagonists, e.g., methotrexates, bind tightly with the intracellular enzyme dihydrofolate reductase ultimately leading to cell death resulting from an inability to synthesize pyrimidines. Toxicities associated with the use of these compounds include alopecia, myelosuppression, vomiting, nausea, and cerebellar ataxia, among others.
Plant alkaloids such as vincristine, vinblastine or podophyllotoxins etoposide and tenisposide generally inhibit mitosis and DNA synthesis and RNA dependent protein synthesis. Toxicities of these drugs are similar to those described above and include myopathy, myelosuppression, peripheral neuropathy, vomiting, nausea and alopecia.
Antitumor antibiotics such as doxorubicin, daunorubicin and actinomycin act as intercalators of DNA, preventing cell replication, inhibiting synthesis of DNA-dependent RNA and inhibiting DNA polymerase.Bleomycin causes scission of DNA and mitomycin acts as inhibitor of DNA synthesis by bifunctional alkylation. Toxicities of these antibiotics are numerous and severe and include necrosis, myelosuppression, anaphylactic reactions, anorexia, dose-dependent cardiotoxicity and pulmonary fibrosis.
Other compounds used for chemotherapeutic treatment of cancer are inorganic ions such as cisplatin, biologic response modifiers such as interferon, enzymes and hormones. All these compounds, similarly to those mentioned above, are accompanied by toxic adverse reactions.
Accordingly, it would be extremely advantageous to provide safe and non-toxic chemotherapeutic compositions which would effectively inhibit and/or suppress tumor cell proliferation and/or neoplastic growth. Furthermore, it would be extremely advantageous to provide safe, effective and non-toxic chemotherapeutic compositions that are easy to 5 administer.
The identification of safe, effective, non-toxic, and orally administrable organic compounds capable of depressing or regressing malignant tumor growth in mammals and the use of such compounds to treat cancer is therefore desirable and the object of this invention.
Several naturally-occurring alkaloids obtained from Vinca rosea have demonstrated efficacy in treating malignancies. Examples of these include leurosine, vincaleukoblastine or vinblastine, leuroformine; leurosidine (vinrosidine) and leurocristine or vincristine; deoxy vinblastine "A" and "B"; 4-desacetoxyvinblastine; 4-desacetoxy-3-hydroxyvinblastine; leurocolombine and vincadioline. At least two of these alkaloids, vinblastine and vincristine, are now marketed as drugs for treating malignancies, especially leukemias and related diseases in humans.
Chemical modification of the vinca alkaloids has been relatively limited. Among the successful modifications of physiologically-active alkaloids has been the preparation of dihydro vinblastine and the replacement of the acetyl group at C-4 (carbon no. 4 of the vinblastine ring system) with higher alkanoyl group or with unrelated acyl groups. One of the derivatives in which a chloracetyl group replaced the C-4 acetyl group of vinblastine has been shown to be a useful intermediate for the preparation of structurally modified vinblastine compounds in which an N,N-dialkylglycyl group replaced the C-4 acetyl group of vinblastine. C-3 carboxamide derivatives of vinblastine, vincristine, vincadioline etc. have also been prepared and found to be active anti-tumor agents. Certain of the amide derivatives actually approach the activity of vincristine against these tumors. One of these amides, 4-desacetyl vinblastine C-3 carboxamide or vindesine has been found active in certain leukemias.